rs138670030

Variant names:

• chr9-136673217-G-A
• rs138670030
• NM_006412.4:c.*535C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006412.4(AGPAT2):​c.*535C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 152,866 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (68 hom., cov: 34)
  • Exomes 𝑓: 0.023 (0 hom.)
• Consequence: AGPAT2 NM_006412.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00200

Genes affected

AGPAT2 (HGNC:325): (1-acylglycerol-3-phosphate O-acyltransferase 2) This gene encodes a member of the 1-acylglycerol-3-phosphate O-acyltransferase family. The protein is located within the endoplasmic reticulum membrane and converts lysophosphatidic acid to phosphatidic acid, the second step in de novo phospholipid biosynthesis. Mutations in this gene have been associated with congenital generalized lipodystrophy (CGL), or Berardinelli-Seip syndrome, a disease characterized by a near absence of adipose tissue and severe insulin resistance. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-136673217-G-A is Benign according to our data. Variant chr9-136673217-G-A is described in ClinVar as [Benign]. Clinvar id is 365900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGPAT2	NM_006412.4	c.*535C>T		3_prime_UTR_variant	Exon 6 of 6	ENST00000371696.7	NP_006403.2
AGPAT2	NM_001012727.2	c.*535C>T		3_prime_UTR_variant	Exon 5 of 5		NP_001012745.1
AGPAT2	XM_047422636.1	c.*535C>T		3_prime_UTR_variant	Exon 6 of 6		XP_047278592.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGPAT2	ENST00000371696	c.*535C>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_006412.4	ENSP00000360761.2
AGPAT2	ENST00000371694	c.*535C>T		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000360759.3

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3137 AN: 152174 Hom.: 66 Cov.: 34

Gnomad AFR AF: 0.00372

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.0693

Gnomad SAS AF: 0.0467

Gnomad FIN AF: 0.0552

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0234

Gnomad OTH AF: 0.0148

GnomAD4 exome AF: 0.0226 AC: 13 AN: 574 Hom.: 0 Cov.: 0 AF XY: 0.0229 AC XY: 7 AN XY: 306

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0455

Gnomad4 EAS exome AF: 0.0833

Gnomad4 SAS exome AF: 0.0625

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0195

Gnomad4 OTH exome AF: 0.0526

GnomAD4 genome AF: 0.0207 AC: 3156 AN: 152292 Hom.: 68 Cov.: 34 AF XY: 0.0232 AC XY: 1728 AN XY: 74458

Gnomad4 AFR AF: 0.00370

Gnomad4 AMR AF: 0.00876

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.0704

Gnomad4 SAS AF: 0.0470

Gnomad4 FIN AF: 0.0552

Gnomad4 NFE AF: 0.0234

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0254 Hom.: 10

Bravo AF: 0.0152

Asia WGS AF: 0.0600 AC: 207 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital generalized lipodystrophy type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.6
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138670030; hg19: chr9-139567669;